title: Breast cancer resistance protein-mediated efflux of luteolin glucuronides in HeLa cells overexpressing UDP-glucuronosyltransferase 1A9.
abstract: OBJECTIVE
  UDP-glucuronosyltransferases (UGTs) are responsible for the formation of glucuronides of polyphenolic flavonoids. This study investigated the UGT1A9-mediated glucuronidation of luteolin and the kinetics of luteolin glucuronide efflux.
  
  
  METHODS
  HeLa cells overexpressing UGT1A9 (HeLa-UGT1A9) were used to determine the kinetics of breast cancer resistance protein (BCRP)-mediated transport of luteolin glucuronides. Human UGT isoforms were used to determine glucuronidation rates.
  
  
  RESULTS
  UGT1A9 was found to catalyze the production of four luteolin glucuronides, including three known monoglucuronides and a novel 3', 4'-diglucuronide. Ko143, a potent specific inhibitor of BCRP, significantly inhibited efflux of luteolin monoglucuronides from HeLa1A9 cells and increased their intracellular levels in a dose-dependent manner. The formation of luteolin diglucuronide was observed when intracellular concentration of total monoglucuronides went above 0.07 nM.
  
  
  CONCLUSIONS
  Intracellular accumulation of diglucuronide was detected at high monoglucuronide concentrations (>0.07 nM). Diglucuronide production is speculated to be a compensatory pathway for luteolin disposition.
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China, 510006.
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.forename: Wei-Ying
authors.initials: WY
authors.lastname: Chen
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.forename: Ling-Na
authors.initials: LN
authors.lastname: Dong
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Peng
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Liu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D047311:Luteolin / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054659:Diketopiperazines; D020719:Glucuronides; D006576:Heterocyclic Compounds, 4 or More Rings; D009363:Neoplasm Proteins; C000715591:UGT1A9 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D000241:Adenosine; D047311:Luteolin